Our clinical research continues to address several important aspects of the following questions: how to optimally use and administer multi-class combination anti-retroviral therapy;how to integrate immune based therapies within a framework of ongoing antiretroviral therapy;how to determine the optimal time for initiation of antiretroviral strategy in order to preserve and reconstitute immune function while at the same time minimizing long-term antiretroviral toxicities, and what are some of the predictive factors for the development of adverse consequences of progressive HIV infection both on and off antiretroviral medications. One of the greatest unmet goals in current antiretroviral strategies is to develop a successful means of depleting, perhaps ultimately even eradicating, the reservoir of latent virus that remains in host lymphocytes, macrophages, and other cellular reservoirs even after levels of plasma virus are suppressed below the limits of conventional detection methods. If such eradication could be achieved without inflicting unacceptable levels of drug toxicity and/or involving radical therapies that could not easily be broadly adapted to the larger community of HIV-infected individuals, it is conceivable that a combination treatment approach could be developed to purge HIV-infected hosts of latent virus that would not rebound once antiretroviral therapy was discontinued. In this regard, we are assisting other NIAID and NCI investigators in the planning and initial preclinical testing of a novel "immuno-toxin", a monoclonal antibody linked with pseudomonas exotoxin, that may have direct antiviral activity by virtue of its affinity for HIV-infected cells. The potential value of this immunotoxin is that, unlike conventional antiretroviral medications that target various stages of the viral replication cycle, in vivo and animal studies have shown that this agent selectively destroys host cells harboring the virus and expressing viral antigen on the cell surface. Once approved for human testing, the goal of upcoming clinical trials will be to determine safety as well as to determine whether addition of this agent to effective HAART further depletes the latent viral reservoir to a degree not achievable by the latter agents alone. At the NIH Clinical Center we are also fully operational as one of the trial and substudy sites for the "START" study (Strategic Timing of AntiRetroviral Treatment) aimed at determining whether early introduction of ART in previously-untreated patients translates into better clinical outcomes. Current Department of Health and Human Services Antiretroviral Guidelines recommend the initiation of HAART for HIV-infected individuals with CD4 cell counts of 500 cells/L or less. However, those recommendations are controversial in that they are based upon the outcomes of large observational trials and not data from a randomized clinical trial. In order to address this question more rigorously, the START trial is a large multi-national trial enrolling antiretroviral-naive HIV-infected individuals with CD4 cell counts above 500 cells/L and randomly assigning them either to begin HAART immediately or to delay the start of HAART until the CD4 cell count falls below 350 cells/L. The primary goal of this 4-5 year trial will be to compare the two arms in terms of the cumulative incidence of adverse consequences ascribable either to progressive HIV infection or to the toxicities of HAART itself. Finally, we also continue our efforts to improve access to clinical trials by local minority populations through an outreach that includes a close relationship with local clinics for medically under-served populations.